Sterol-regulatory-element-binding protein 2 and nuclear factor Y control human farnesyl diphosphate synthase expression and affect cell proliferation in hepatoblastoma cells

Kenji Ishimoto; Keisuke Tachibana; Ikuko Hanano; Daisuke Yamasaki; Hiroki Nakamura; Megumi Kawai; Yasuomi Urano; Toshiya Tanaka; Takao Hamakubo; Juro Sakai; Tatsuhiko Kodama; Takefumi Doi

doi:10.1042/BJ20091511

Sterol-regulatory-element-binding protein 2 and nuclear factor Y control human farnesyl diphosphate synthase expression and affect cell proliferation in hepatoblastoma cells

Biochem J. 2010 Jul 15;429(2):347-57. doi: 10.1042/BJ20091511.

Authors

Kenji Ishimoto¹, Keisuke Tachibana, Ikuko Hanano, Daisuke Yamasaki, Hiroki Nakamura, Megumi Kawai, Yasuomi Urano, Toshiya Tanaka, Takao Hamakubo, Juro Sakai, Tatsuhiko Kodama, Takefumi Doi

Affiliation

¹ Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.

PMID: 20450493
DOI: 10.1042/BJ20091511

Abstract

FDPS (farnesyl diphosphate synthase) catalyses the formation of farnesyl diphosphate, a key intermediate in the synthesis of cholesterol and isoprenylated cellular metabolites. FDPS is also the molecular target of nitrogen-containing bisphosphonates, which are used as bone-antiresorptive drugs in various disorders. In the present study, we characterized the sterol-response element and NF-Y (nuclear factor Y)-binding site in the human FDPS promoter. Using a luciferase assay, electrophoretic mobility-shift assay and chromatin immunoprecipitation assay, we demonstrated that these elements are responsible for the transcription of the FDPS gene, and that its transcriptional activation is mediated by SREBP-2 (sterol-regulatory-element-binding protein 2) and NF-Y. We also investigated whether sterol-mediated FDPS expression is involved in the cell proliferation induced by zoledronic acid, an FDPS inhibitor. We show that the SREBP-2- and NF-Y-mediated regulation of FDPS gene transcription modulates cell proliferation. These results suggest that SREBP-2 and NF-Y are required to trigger cell proliferation through the induction of FDPS expression and that the pharmacological action of zoledronic acid is involved in this pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Base Sequence
Binding Sites / genetics
Bone Density Conservation Agents / pharmacology
CCAAT-Binding Factor / antagonists & inhibitors
CCAAT-Binding Factor / genetics
CCAAT-Binding Factor / metabolism*
Cell Line, Tumor
Cell Proliferation / drug effects
Conserved Sequence
DNA Primers / genetics
DNA, Neoplasm / genetics
DNA, Neoplasm / metabolism
Diphosphonates / pharmacology
Gene Knockdown Techniques
Geranyltranstransferase / biosynthesis
Geranyltranstransferase / genetics*
Hepatoblastoma / genetics*
Hepatoblastoma / metabolism*
Hepatoblastoma / pathology
Humans
Imidazoles / pharmacology
Liver Neoplasms / genetics*
Liver Neoplasms / metabolism*
Liver Neoplasms / pathology
Molecular Sequence Data
Mutagenesis, Site-Directed
Promoter Regions, Genetic
RNA, Small Interfering / genetics
Sequence Homology, Nucleic Acid
Sterol Regulatory Element Binding Protein 2 / antagonists & inhibitors
Sterol Regulatory Element Binding Protein 2 / genetics
Sterol Regulatory Element Binding Protein 2 / metabolism*
Sterols / metabolism
Transcriptional Activation
Transfection
Zoledronic Acid

Substances

Bone Density Conservation Agents
CCAAT-Binding Factor
DNA Primers
DNA, Neoplasm
Diphosphonates
Imidazoles
RNA, Small Interfering
SREBF2 protein, human
Sterol Regulatory Element Binding Protein 2
Sterols
nuclear factor Y
Zoledronic Acid
Geranyltranstransferase